ABSTRACT The lack of a clear understanding of the pathophysiology of Cutaneous T cell Lymphoma (CTCL) and in particular its aggressive leukemic form Szary Syndrome, has impeded therapeutic advances, and current treatments are only palliative. Although CTCL is a relatively rare disease, Moffitt Cancer Center Malignant Hematology and USF Dermatology Departments manages about 100 new patients with CTCL annually. This study represents a concerted effort by a team of clinical investigators and translational immunologists at Moffitt to identify new effective treatments for CTCL patients with aggressive disease, based on the discovery of key molecular regulators of Szary Syndrome development and growth. Specifically, our new mouse models indicate that Special AT-rich region binding protein 1 (SATB1), a master genomic organizer and a key regulator of T-cell development and maturation, prevents mature T cell malignization by repressing crucial pathogenic drivers of Szary cells. Our central hypothesis is that SATB1 acts as a tumor suppressor in CTCL, by repressing STAT5 activation, chemokine receptors that govern T cell homing to the skin and transcription factors commonly de-regulated in malignant T cells. Accordingly, restoring SATB1 expression by targeting histone methylation and de-acetylation will avert the malignant phenotype of Szary cells. We will leverage a growing collection of aphaeresis specimens and unique mouse models to dissect the epigenetic mechanisms governing the pathogenesis of Szary Syndrome, with the overarching goal of subsequently targeting them through more effective interventions in our clinic. In Aim 1, we will elucidate how SATB1 silencing drives the pathogenesis of CTCL. Based on our preliminary results, our hypothesis is that Satb1 silencing cooperates with Notch signaling to elicit a STAT5-, CCR10-, IKZF2/HELIOS-dependent transcriptional program leading to the progressive expansion, skin homing and malignant transformation of post-thymic CD4 T cells. In Aim 2, we will define the complementary mechanisms leading to epigenetic silencing of the SATB1 locus in Szary Syndrome. We will test the hypothesis that SATB1 is silenced in Szary cells through a combination of histone methylation at K27 and K9 that, along with and lysine de-acetylation, resulting in significant changes in chromatin accessibility. In Aim 3, we will leverage our new biological understanding to identify the combination of epigenetic drugs that more effectively restore SATB1 expression and thwart oncogenic signals in Szary cells. Our work will exert a profound effect in the field by elucidating how epigenetic repression of the master genomic organizer SATB1 governs the malignant transformation of mature CD4 T cells in coordination with NOTCH signaling, leading to fatal skin accumulation of lymphocytes in Szary patients. This mechanistic insight will inform the most effective combination of drugs needed to de-repress the SATB1 locus and antagonize oncogenic signals, which will overturn malignant Szary cells. This biological understanding will be followed by clinical interventions at Moffitt for patients with aggressive CTCL, including Szary Syndrome.